Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients

ABSTRACT

Methods for preparing dry powders having hydrophobic and hydrophilic components comprise combining solutions of the components and spray drying them simultaneously in a spray dryer. The hydrophilic and hydrophobic component are separately dissolved in separate solvents and directed simultaneously through a nozzle, usually a coaxial nozzle, into the spray dryer. The method provides dry powders having relatively uniform characteristics.

This application is a continuation-in-part of Provisional ApplicationSer. No. 60/034,837, filed on Dec. 31, 1996, the full disclosure ofwhich is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to dry powder compositions andmethods for their preparation and use. In particular, the presentinvention relates to methods for spray drying pharmaceutical and othercompositions comprising a hydrophobic drug or other component and ahydrophilic excipient or other component.

Over the years, certain drugs have been sold in formulations suitablefor oral inhalation (pulmonary delivery) to treat various conditions inhumans. Such pulmonary drug delivery formulations are designed to beinhaled by the patient so that the active drug within the dispersionreaches the lung. It has been found that certain drugs delivered to thelung are readily absorbed through the alveolar region directly intoblood circulation. Such pulmonary delivery can be effective both forsystemic delivery and for localized delivery to treat diseases of thelungs.

Pulmonary drug delivery can itself be achieved by different approaches,including liquid nebulizers, aerosol-based metered dose inhalers(MDI's), and dry powder dispersion devices. Aerosol-based MDI's arelosing favor because they rely on the use of chlorofluorocarbons(CFC's), which are being banned because of their adverse effect on theozone layer. Dry powder dispersion devices, which do not rely on CFCaerosol technology, are promising for delivering drugs that may bereadily formulated as dry powders.

The ability to deliver pharmaceutical compositions as dry powders,however, is problematic in certain respects. The dosage of manypharmaceutical compositions is often critical, so it is desirable thatdry powder delivery systems be able to accurately, precisely, andreliably deliver the intended amount of drug. Moreover, manypharmaceutical compositions are quite expensive. Thus, the ability toefficiently formulate, process, package, and deliver the dry powderswith a minimal loss of drug is critical. With dry powder drug delivery,both the delivered dose efficiency, i.e. the percentage of drug from aunit dose receptacle which is aerosolized and delivered from a deliverydevice, and the median particle size distribution, i.e. the deviationfrom the median size, are critical to the successful delivery of powdersto a patient's lungs.

A particularly promising approach for the pulmonary delivery of drypowder drugs utilizes a hand-held device with a hand pump for providinga source of pressurized gas. The pressurized gas is abruptly releasedthrough a powder dispersion device, such as a venturi nozzle, and thedispersed powder made available for patient inhalation. Whileadvantageous in many respects, such hand-held devices are problematic ina number of other respects. The particles being delivered are usuallyless than 5 μm in size, making powder handling and dispersion moredifficult than with larger particles. The problems are exacerbated bythe relatively small volumes of pressurized gas, which are availableusing hand-actuated pumps. In particular, venturi dispersion devices areunsuitable for difficult-to-disperse powders when only small volumes ofpressurized gas are available with the handpump. Another requirement forhand-held and other powder delivery devices is efficiency. High deviceefficiency in delivering the drug to the patient with the optimal sizedistribution for pulmonary delivery is essential for a commerciallyviable product.

Spray drying is a conventional chemical processing unit operation usedto produce dry particulate solids from a variety of liquid and slurrystarting materials. The use of spray drying for the formulation of drypowder pharmaceuticals is known, but has usually been limited to spraydrying of hydrophilic drugs in aqueous solutions, usually in combinationwith hydrophilic excipients. Many drugs, however, are hydrophobic,preventing spray drying in aqueous solutions. While spray drying ofhydrophobic materials can often be accomplished using an organicsolvent, the use of such non-aqueous solvents generally limits theability to simultaneously spray dry a hydrophilic excipient.

For these reasons, it would be desirable to provide improved methods forspray drying pharmaceutical and other compositions which comprise bothhydrophobic and hydrophilic components, such as hydrophobic drugs andhydrophilic excipients. Such spray drying methods should be compatiblewith a wide variety of hydrophobic drugs as well as conventionalhydrophilic excipients, such as povidone (polyvinylpyrrolidone) andother water soluble polymers, citric acid, mannitol, pectin and otherwater soluble carbohydrates, and particularly with those excipientswhich are accepted for use in inhalation formulations, such as lactose,sodium chloride, and sodium citrate. Such spray drying methods willpreferably produce particles having a uniform size distribution, with amean particle size below 10 μm, preferably below 5 μm, and a standarddeviation less than or equal to ±2 μm. Such powders should furtherexhibit uniform composition from batch to batch so that any tendency forparticles of different compositions and/or sizes to separate in thelungs will have a reproducible impact on the therapeutic effect.Additionally, such spray drying methods should provide for dry powderswhich are physically and chemically stable and which have low levels ofany residual organic solvents or other components which might be used inthe spray drying process. At least some of the above objectives will bemet by the various embodiments of the present invention which aredescribed in detail below.

2. Description of the Background Art

Methods for spray drying hydrophobic and other drugs and components aredescribed in U.S. Pat. Nos. 5,000,888; 5,026,550; 4,670,419, 4,540,602;and 4,486,435. Bloch and Speison (1983) Pharm. Acta Helv 58:14-22teaches spray drying of hydrochlorothiazide and chlorthalidone(lipophilic drugs) and a hydrophilic adjuvant (pentaerythritol) inazeotropic solvents of dioxane-water and 2-ethoxyethanol-water. A numberof Japanese Patent application Abstracts relate to spray drying ofhydrophilic-hydrophobic product combinations, including JP 806766; JP7242568; JP 7101884; JP 7101883; JP 71018982; JP 7101881; and JP4036233. Other foreign patent publications relevant to spray dryinghydrophilic-hydrophobic product combinations include FR 2594693; DE2209477; and WO 88/07870.

WO 96/09814 describes spray dried pharmaceutical powders. In particular,Example 7 describes spray drying budesonide and lactose in ethanol wherethe budesonide is partially soluble and the lactose is insoluble. U.S.Pat. Nos. 5,260,306; 4,590,206; GB 2 105 189; and EP 072 046 describe amethod for spray drying nedocromil sodium to form small particlespreferably in the range from 2 to 15 Am for pulmonary delivery. U.S.Pat. No. 5,376,386, describes the preparation of particulatepolysaccharide carriers for pulmonary drug delivery, where the carrierscomprise particles sized from 5 to 1000 μm. Mumenthaler et al. (1994)Pharm. Res. 11:12 describes recombinant human growth hormone andrecombinant tissue-type plasminogen activator. WO 95/23613 describespreparing an inhalation powder of DNase by spray drying usinglaboratory-scale equipment. WO 91/16882 describes a method for spraydrying proteins and other drugs in liposome carriers.

The following applications assigned to the assignee of the presentapplication each describe that spray drying may be used to prepare drypowders of biological macromolecules; co-pending application Ser. No.08/644,681, filed on May 8, 1996, which was a continuation-in-part ofapplication Ser. No. 08/423,515, filed on Apr. 14, 1995; applicationSer. No. 08/383,475, filed Feb. 1, 1995, now abandoned which was acontinuation-in-part of application Ser. No. 08/207,472, filed on Mar.7, 1994, now abandoned; application Ser. No. 08/472,563, filed on Apr.14, 1995 now abandoned, which was a continuation-in-part of applicationSer. No. 08/417,507, filed on Apr. 4, 1995, now abandoned, which was acontinuation of application Ser. No. 08/044,358, filed on Apr. 7, 1993,now abandoned; application Ser. No. 08/232,849, filed on Apr. 25, 1994,U.S. Pat. No. 5,607,915, which was a continuation of application Ser.No. 07/953,397, now abandoned. WO 94/07514 claims priority from Ser. No.07/953,397, now abandoned. WO 95/24183 claims priority from Ser. Nos.08/207,472 and 08/383,475.

SUMMARY OF THE INVENTION

According to the present invention, methods for spray drying hydrophobicdrugs and other materials are provided which overcome at least some ofthe deficiencies noted above with respect to prior spray dryingprocesses. In particular, the spray drying methods of the presentinvention permit the simultaneous spray drying of the hydrophobiccomponent with a hydrophilic component, such as a hydrophilicpharmaceutical excipient, under conditions which result in a dry powdercomprising mixtures of both the hydrophilic and hydrophobic components.Although the methods of the present invention are particularly usefulfor forming pharmaceutical compositions where the hydrophobic componentis a hydrophobic drug, usually present at from 0.01% to 95% of thepowder, and the hydrophilic component is a hydrophilic excipient,usually present at from 99.99% to 5% of the powder, the methods may beapplied more broadly to form dry powders comprising a variety ofhydrophobic and hydrophilic components at different concentrationranges, including hydrophilic drugs and hydrophobic excipients.

The spray drying methods of the present invention are compatible with atleast most hydrophilic pharmaceutical excipients, particularly includingmannitol, povidone, pectin, lactose, sodium chloride, and sodiumcitrate. Use of the latter three excipients is particularly preferredfor powders intended for pulmonary delivery as they are "generallyrecognized as safe" (GRAS) for such applications. The methods are alsosuitable for use with numerous hydrophobic drugs and nutrients,including steroids and their salts, such as budesonide, testosterone,progesterone, estrogen, flunisolide, triamcinolone, beclomethasone,betamethasone; dexamethasone, fluticasone, methylprednisolone,prednisone, hydrocortisone, and the like; peptides, such as cyclosporinand other water insoluble peptides; retinoids, such as all-cis retinoicacid, 13-trans retinoic acid, and other vitamin A and beta carotenederivatives; vitamins D, E, and K and water insoluble precursors andderivatives thereof; prostaglandins and leukotrienes and theiractivators and inhibitors including prostacyclin (epoprostanol), andprostaglandins E₁ E₂ ; tetrahydrocannabinol; lung surfactant lipids;lipid soluble antioxidants; hydrophobic antibiotics and chemotherapeuticdrugs such as amphotericin B, adriamycin, and the like.

The spray drying methods can produce a uniform particle sizedistribution. For example, the mean particle diameter can be controlledbelow 10 μm, preferably below 5 μm, with a size distribution (standarddeviation) less than ±2 μm. The particles of the powders so producedhave a minimum batch-to-batch variability in composition, and arephysically and chemically stable. The powders have minimum residualorganic solvents to the extent they may have been used in the spraydrying process.

In particular, the method of the present invention comprises preparingan aqueous solution of a hydrophilic component and an organic solutionof a hydrophobic component in an organic solvent. The aqueous solutionand the organic solution are simultaneously spray dried to formparticles comprising a mixture of the hydrophilic and hydrophobiccomponents. Usually the hydrophilic component has a concentration in theaqueous solution from 1 mg/ml to 100 mg/ml, preferably from 5 mg/ml to60 mg/ml. The hydrophobic component has a solubility in the organicsolution of at least 0.01 mg/ml, preferably at least 0.05 mg/ml. Theconcentration of the hydrophobic component in the organic solution isusually in the range from 0.01 mg/ml to 10 mg/ml, preferably from 0.05mg/ml to 5 mg/ml. Preferred organic solvents include alcohols, ketones,ethers, aldehydes, hydrocarbons, and polar aprotic solvents, and thelike and mixtures thereof. The use of a separate aqueous and organicsolution to carry the hydrophilic and hydrophobic components,respectively, is advantageous in that it allows a much broader range ofselection for the organic solvent, since the organic solvent does notalso have to solubilize the hydrophilic component. It is alsoparticularly advantageous for spray drying hydrophobic components andhydrophilic components which are chemically or physically incompatiblein solution, since the solutions of the hydrophobic components andhydrophilic components do not reside together until they are passingthrough the spray nozzle during spray drying. This severely minimizesthe contact time between the two solutions before drying occurs, andhence minimizes the potential for undesirable reactions to occur.Usually, the aqueous solution and organic solution will be spray driedthrough a common spray nozzle, more usually through a coaxial spraynozzle.

Powders prepared by any of the above methods will be collected from thespray dryer in a conventional manner for subsequent use. For use aspharmaceuticals and other purposes, it will frequently be desirable todisrupt any agglomerates which may have formed by screening or otherconventional techniques. For pharmaceutical uses, the dry powderformulations will usually be measured into a single dose, and the singledose sealed into a package. Such packages are particularly useful fordispersion in dry powder inhalers, as described in detail below.Alternatively, the powders may be packaged in multiple-dose containers.

The present invention further comprises dry powder compositions producedaccording to the methods described above, as well as unit dose andmultidose packages of such dried powder compositions containing atherapeutically effective amount of the dry powder.

The present invention further provides methods for aerosolizing a drypowder composition comprising the steps of providing an amount of drypowder composition produced by any of the methods described above andsubsequently dispersing the dry powder composition into a flowing gasstream.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating a spray drying system suitablefor performing the methods of the present invention.

FIG. 2. illustrates a coaxial spray nozzle used in spray drying asdescribed in the Experimental section.

FIG. 3 illustrates a two-tube spray nozzle used in spray drying asdescribed in the Experimental section.

FIG. 3A is a detail cross-section view of region 3A in FIG. 3.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The present invention relates to methods for preparing compositionscomprising ultrafine dry powders having both hydrophobic and hydrophiliccomponents. The methods are particularly suitable for producingultrafine pharmaceutical dry powders where the hydrophobic component isa hydrophobic drug and the hydrophilic component is a hydrophilicexcipient. The present invention, however, may find use for preparing avariety of other compositions including pharmaceutical compositionshaving hydrophilic drugs and hydrophobic excipients and compositionsintended for non-pharmaceutical applications. The methods rely on spraydrying liquid media in which the components are solubilized orsuspended. In particular, the hydrophobic and hydrophilic components aresolubilized in separate liquid media and the media are simultaneouslyspray dried through a common nozzle.

The term "hydrophobic component" refers to materials which are insolubleor sparingly or poorly soluble in water. As used herein, suchcompositions will have a solubility below 5 mg/ml, usually below 1mg/ml. Exemplary hydrophobic drugs include certain steroids, such asbudesonide, testosterone, progesterone, estrogen, flunisolide,triamcinolone, beclomethasone, betamethasone; dexamethasone,fluticasone, methylprednisolone, prednisone, hydrocortisone, and thelike; certain peptides, such as cyclosporin cyclic peptide, retinoids,such as all-cis retinoic acid, 13-trans retinoic acid, and other vitaminA and beta carotene derivatives; vitamins D, E, and K and waterinsoluble precursors and derivatives thereof; prostagladins andleukotrienes and their activators and inhibitors including prostacyclin(epoprostanol), and prostaglandins E₁ E₂ ; tetrahydrocannabinol; lungsurfactant lipids; lipid soluble antioxidants; hydrophobic antibioticsand chemotherapeutic drugs such as amphotericin B and adriamycin and thelike.

By "hydrophilic component," it is meant that the component is highlysoluble in water and frequently capable of swelling and formation ofreversible gels. Typical aqueous solubilities of hydrophilic componentswill be greater than 5 mg/ml, usually greater than 50 mg/ml, oftengreater than 100 mg/ml and often much higher. In addition to theirhydrophilic nature, the pharmaceutical excipients will generally beselected to provide stability, dispersibility, consistency and/orbulking characteristics to enhance the uniform pulmonary delivery of thedried powder composition to a patient. For pulmonary delivery, theexcipients must be capable of being taken into the lungs with nosignificant adverse toxicological effects on the lungs. Exemplaryhydrophilic excipients include carbohydrates and other materialsselected from the group consisting of lactose, sodium citrate, mannitol,povidone, pectin, citric acid, sodium chloride, water soluble polymers,and the like. Particularly preferred are lactose, sodium chloride,sodium citrate, and citric acid which are generally accepted forpulmonary delivery in dry powder formulations.

The phrase "ultrafine dry powder" means a powder composition comprisinga plurality of discrete, dry particles having the characteristics setforth below. In particular, the dry particles will have an averageparticle size below 10 μm, usually below 5 μm, preferably being in therange from 0.4 to 5 μm, more preferably from 0.4 to 4 μm. The averageparticle size of the powder will be measured as mass median diameter(MMD) by conventional techniques. A particular powder sizing techniqueuses a centrifugal sedimentary particle size analyzer (Horiba Capa 700).The powders will be capable of being readily dispersed in an inhalationdevice and subsequently inhaled by a patient so that the particles areable to penetrate into the alveolar regions of the lungs.

Of particular importance to the present invention, the ultrafine dryparticle compositions produced by the method will have particle sizedistributions which enable them to target the alveolar region of thelung for pulmonary delivery of locally acting steroids, systemicallyacting proteins, and other biologically active materials that can beadministered to or through the lungs. Such compositions advantageouslymay be incorporated into unit dosage and other forms without furthersize classification. Usually, the ultrafine dry powders will have a sizedistribution where at least 90% of the powder by weight will compriseparticles having an average size in the range from 0.1 μm to 7 μm, withpreferably at least 85% being in the range from 0.4 μm to 5 μm.Additionally, it is desirable that the particle size distribution avoidhaving an excess amount of particles with very small average diameters,i.e., below 0.4 μm.

The term "dry" means that the particles of the powder have a moistureand residual solvent content such that the powder is physically andchemically stable in storage at room temperature and is readilydispersible in an inhalation device to form an aerosol. Usually, themoisture and residual solvent content of the particles is below 10% byweight, usually being below 5% by weight, preferably being below 3% byweight, or lower. The moisture and residual solvent content will usuallybe controlled by the drying conditions, as described in more detailbelow. The term "dry" further means that the particles of the powderhave a moisture and residual solvent content such that the powder isreadily dispersible in an inhalation device to form an aerosol. In somecases, however, non-aqueous medium may be used for dispersing thecomponents, in which case the aqueous content may approach zero.

The term "therapeutically effective amount" is the amount present in thecomposition that is needed to provide the desired level of hydrophobicdrug in the subject to be treated to give the anticipated physiologicalresponse. This amount is determined for each drug on a case-by-casebasis. The term "physiologically effective amount" is that amountdelivered to a subject to give the desired palliative or curativeeffect. This amount is specific for each drug and its ultimate approvaldosage level.

The therapeutically effective amount of hydrophobic drug will vary inthe composition depending on the biological activity of the drugemployed and the amount needed in a unit dosage form. Because thesubject powders are dispersible, it is highly preferred that they bemanufactured in a unit dosage form in a manner that allows for readymanipulation by the formulator and by the consumer. This generally meansthat a unit dosage will be between about 0.5 mg and 15 mg of totalmaterial in the dry powder composition, preferably between about 1 mgand 10 mg. Generally, the amount of hydrophobic drug in the compositionwill vary from about 0.01 w/w to about 95% w/w. Most preferably thecomposition will be about 0.05% w/w to about 25% w/w drug.

Referring now to FIG. 1, processes according to the present inventionfor preparing dispersible dry powders of hydrophobic and hydrophiliccomponents comprise an atomization operation 10 which produces dropletsof a liquid medium which are dried in a drying operation 20. Drying ofthe liquid droplets results in formation of the discrete particles whichform the dry powder compositions which are then collected in aseparation operation 30. Each of these unit operations will be describedin greater detail below.

The atomization process 10 may utilize any one of several forms ofatomizers, so long as the atomizer is specially designed to deliver theliquid containing the hydrophobic components and the liquid containingthe hydrophilic components separately to the lower portion of theatomizer, for which FIG. 2 and FIG. 3 serve as nonlimiting examples. Theatomization process increases the surface area of the starting liquid.Due to atomization there is an increase in the surface energy of theliquid, the magnitude of which is directly proportional to the surfacearea increase. The source of this energy increase depends on the type ofatomizer used. Any atomizer (centrifugal, sonic, pressure, two fluid)capable of producing droplets with a mass median diameter of less thanabout 20 μm could be used. Preferred for the present invention is theuse of two fluid atomizers where the liquid medium is delivered througha nozzle concurrently with a high pressure gas stream. Particularlypreferred is the use of two-fluid atomization nozzles as described incopending application Ser. No. 08/644,681, which is capable of producingdroplets having a median diameter less than 20 μm.

The atomization gas will usually be nitrogen which has been filtered orotherwise cleaned to remove particulates and other contaminants.Alternatively, other gases, such as air may be used. The atomization gaswill be pressurized for delivery through the atomization nozzle,typically to a pressure above 5 psig, preferably being above 10 psig.Although flow of the atomization gas is generally limited to sonicvelocity, the higher delivery pressures result in an increasedatomization gas density. Such increased gas density has been found toreduce the droplet size formed in the atomization operation. Smallerdroplet sizes, in turn, result in smaller particle sizes. Theatomization conditions, including atomization gas flow rate, atomizationgas pressure, liquid flow rate, and the like, will be controlled toproduce liquid droplets having an average diameter below 20 Am asmeasured by phase doppler velocimetry.

The drying operation 20 will be performed next to evaporate liquid fromthe droplets produced by the atomization operation 10. Usually, thedrying will require introducing energy to the droplets, typically bymixing the droplets with a heated gas which causes evaporation of thewater or other liquid medium. Preferably, the heated gas stream willflow concurrently with the atomized liquid, but it would also bepossible to employ counter-current flow, cross-current flow, or otherflow patterns.

The drying rate may be controlled based on a number of variables,including the droplet size distribution, the inlet temperature of thegas stream, the outlet temperature of the gas stream, the inlettemperature of the liquid droplets, and the manner in which the atomizedspray and hot drying gas are mixed. Preferably, the drying gas streamwill have an inlet temperature of at least 70° C. The outlet temperaturewill usually be at least about 40° C. The drying gas will usually be airor nitrogen which has been filtered or otherwise treated to removeparticulates and other contaminants. The gas will be moved through thesystem using conventional blowers or compressors.

The separation operation 30 will be selected in order to achieve veryhigh efficiency collection of the ultrafine particles produced by thedrying operation 20. Conventional separation operations may be used,although in some cases they should be modified in order to assurecollection of sub-micron particles. In an exemplary embodiment,separation is achieved using a filter medium such as a membrane medium(bag filter), a sintered metal fiber filter, or the like. Alternatively,and often preferably, separation may be achieved using cycloneseparators, although it is usually desirable to provide for high energyseparation in order to assure the efficient collection of sub-micronparticles. The separation operation should achieve collection of atleast 80% of all particles above 1 μm in average particle size,preferably being above 85%, more preferably being above 90%, and evenmore preferably being above 95%, in collection efficiency.

In some cases, a cyclone separator can be used to separate very fineparticles, e.g. 0.1 μm, from the final collected particles. The cycloneoperating parameters can be selected to provide an approximate cutoffwhere particles above about 0.1 μm are collected while particles below0.1 μm are carried over in the overhead exhaust. The presence ofparticles below 0.1 μm in the pulmonary powder is undesirable since theywill generally not deposit in the alveolar regions of the lungs, butinstead will be exhaled.

The present invention relies on proper selection of the liquid medium ormedia for solubilizing the hydrophobic drug or other component andhydrophilic excipient or other component as well as on the manner ofintroducing the component to the spray dryer. In particular, thecompositions are spray dried by forming separate solutions of thehydrophobic drug or other component and the hydrophilic excipient orother component. The separate solutions are then concurrently butseparately introduced to the spray nozzle, typically by passing througha common spray nozzle or nozzles in the spray dryers described above.This method has the advantage that both the hydrophobic drug and thehydrophilic excipient may be easily dissolved since it is generallystraight forward to select compatible solvents capable of fullydissolving only one of the components. By properly directing the twosolutions through a nozzle, such as a coaxial nozzle, spray driedpowders having uniform characteristics may be achieved. This approachhas the additional advantage that it minimizes the amount of organicsolvent required since only the hydrophobic drug or other componentrequires an organic solvent for dissolution. The hydrophilic excipientis dissolved in water.

An exemplary coaxial spray nozzle 100 is illustrated in FIG. 2 andincludes a housing 102 defining a chamber 103. A pair of inlets 104 aredisposed at the top of the housing 102 for receiving the excipientsolution (which is usually delivered at a higher volumetric flow ratethan is the solution of the hydrophobic component). The excipientsolution enters the chamber 103 at a pressure sufficient to achieve adesired flow rate through an outlet orifice 105 at the bottom of thehousing 102. The hydrophobic component solution is fed through a feedtube 106 which usually terminates in a reduced diameter section 108which is disposed coaxially within the orifice 105. The absolute andrelative sizes of the orifice 105 and section 108 of feed tube 106 willdepend on the total flow rates, operating pressures, and nature ofmaterials being spray dried. A specific example is described in theExperimental section hereinafter.

A second exemplary spray nozzle 200 is illustrated in FIGS. 3 and 3A.The nozzle 200 comprises a housing 202, inlets 204 and feed tube 206,generally similar to those described above for nozzle 100. Nozzle 200,however, is not coaxial and instead includes a second, parallel feedtube 208 which receives solution from chamber 203 defined within thehousing 202. Both the feed tube 206 and feed tube 208 have outletorifices 210 and 212, respectively, at their distal ends which directthe solution flow generally horizontally into a mixing chamber 214disposed at the bottom of the housing 202. The mixing chamber is shownto have a conical geometry terminating at its bottom tip in outletpassage 216. The orifices 210 and 212 are preferably oriented as shownin FIG. 3A where the relative angle α is in the range from 5° to 25°,usually about 10°. Such an orifice arrangement results in a vorticalmixing flow in the chamber 214 prior to ejection from the passage 216. Avariety of other mixing chamber designs could also be utilized.

Once the dry powders have been prepared, they may be packaged inconventional ways. For pulmonary pharmaceutical applications, unitdosage forms may comprise a unit dosage receptacle containing a drypowder. The powder is placed within a suitable dosage receptacle in anamount sufficient to provide a subject with drug for a unit dosagetreatment. The dosage receptacle is one that fits within a suitableinhalation device to allow for the aerosolization of the dry powdercomposition by dispersion into a gas stream to form an aerosol and thencapturing the aerosol so produced in a chamber having a mouthpieceattached for subsequent inhalation by a subject in need of treatment.Such a dosage receptacle includes any container enclosing thecomposition known in the art such as gelatin or plastic capsules with aremovable portion that allows a stream of gas (e.g., air) to be directedinto the container to disperse the dry powder composition.

Such containers are exemplified by those shown in U.S. Pat. No.4,227,522 issued Oct. 14, 1980; U.S. Pat. No. 4,192,309 issued Mar. 11,1980; and U.S. Pat. No. 4,105,027 issued Aug. 8, 1978. Suitablecontainers also include those used in conjunction with Glaxo's VentolinRotohaler® brand powder inhaler or Fison's Spinhaler® brand powderinhaler. Another suitable unit-dose container which provides a superiormoisture barrier is formed from an aluminum foil plastic laminate. Thepharmaceutical-based powder is filled by weight or by volume into thedepression in the formable foil and hermetically sealed with a coveringfoil-plastic laminate. Such a container for use with a powder inhalationdevice is described in U.S. Pat. No. 4,778,054 and is used with Glaxo'sDiskhaler® (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237).Preferred dry powder inhalers are those described in U.S. patentapplication Ser. Nos. 08/309,691 and 08/487,184, assigned to theassignee of the present invention. The latter application has beenpublished as WO 96/09085.

The following examples are offered by way of illustration, not by way oflimitation.

Experimental

The following materials were used:

Budesonide (micronized to a median particle size of 1-2 μm; Steraloids)

Lactose monohydrate (NF grade; Foremost Ingredient Group)

Sodium Chloride (reagent grade from VWR and USP grade from EMIndustries)

Deionized water

Ethanol, 200 proof (USP/NF; Spectrum Chemical Mfg. Corp.)

Acetone (for histology; EM Industries)

All batches were spray dried on Buchi 190 Mini Spray Dryers, withnozzles and cyclones that were designed to generate and catch very fineparticles. A Buchi 190 Mini Spray Dryer was used that was modified sothat it was supplied with nitrogen as the gas source and equipped withan oxygen sensor and other safety equipment to minimize the possibilityof explosion. The solution feed rate was 5 ml/minute, inlet temperaturewas adjusted to obtain the outlet temperature noted in each example, andthe top of the cyclone was jacketed and cooled to a temperature of about30° C. for the examples in Table 1, but it was not cooled for theexamples in Table 2. The drying nitrogen flow rate was about 18 SCFM,and the atomizing nitrogen was supplied at 0.5 to 1.5 SCFM. The powderswere further dried in the collector for 5 minutes by maintainingapproximately the outlet temperature and air volume after the feeding ofthe liquid formulation was completed.

Particle size was determined with a Horiba Particle Size Analyzer, modelCAPA 700. Median particle size refers to the volume based particle sizedistribution of the prepared bulk powders determined via centrifugalsedimentation as follows. A sample of the powder was suspended in anappropriate liquid medium (one that minimizes solubilizing theparticle), sonicated to break up the agglomerates, and then centrifuged.The median particle size was determined by measuring the sedimentationrate during centrifugation. This method provides the median size of the"primary" particle, that is, the size of the particles produced by themanufacturing process, plus potential modification during samplepreparation. Because these formulations are composed of both watersoluble and water insoluble materials, it is likely that the suspensionstep during sample preparation does to some extent solubilize part ofthe particle, and thereby modify the particle size that is determined.Therefore, the resultant particle sizes should be viewed as estimatedvalues, rather than absolute values.

Moisture content was determined by the Karl-Fischer Reagent titrimetricmethod.

Delivered dose efficiency refers to a measure of the percentage ofpowder which is drawn out of a blister package and which exits themouthpiece of an inhaler device as described in U.S. patent applicationSer. No. 08/487,184. Delivered dose efficiency is a measure ofefficiency for the powder package/device combination. The test wasperformed by connecting a vacuum system to the device mouthpiece. Thevacuum system was set to be similar to a human inhalation with regard tovolume and flow rate (1.2 liters total at 30 liters/minute). A blisterpackage containing 0.5 to 10 mg of the formulation to be evaluated (5 mgof powder was used for the following examples) was loaded into a devicewhich was held in a testing fixture. The device was pumped and fired,and the vacuum "inhalation" was switched on. The aerosol cloud was thusdrawn out of the device chamber by the vacuum, and the powder wascollected on a filter placed between the mouthpiece and the vacuumsource. The weight of the powder collected on the filter was determined.Delivered dose efficiency was calculated by multiplying this weight byone hundred and dividing by the fill weight in the blister. A highernumber was a better result than a lower number.

MMAD (mass median aerodynamic diameter) refers to a measure of theparticle size of the aerosolized powder. MMAD was determined with anAndersen cascade impactor. In a cascade impactor the aerosolized powder(which was aerosolized using an inhaler device as described in U.S.patent application Ser. No. 08/487,184) enters the impactor via an airstream, and encounters a series of stages that separate particles bytheir aerodynamic diameter (the smallest particles pass farthest downthe impactor). The amount of powder collected on each stage isdetermined gravimetrically, and the mass median aerodynamic diameter isthen calculated.

Coaxial Nozzle System:

Manufacturing procedure:

The budesonide was mixed in the organic solvent until all of thebudesonide was completely dissolved to form a solution, with sonicationif necessary. The excipient was mixed with the water until all of theexcipient was completely dissolved to form a solution, with sonication,if necessary. The solutions were spray dried using a coaxial nozzlespray drying system having a nozzle as illustrated in FIG. 2 or FIG. 3.The FIG. 2 orifice 105 had a diameter of 1.0 mm and outlet tube section108 had an outside diameter of 0.73 mm and an inside diameter of 0.6 mm.The FIG. 3 orifice 216 had a diameter of 1.0 mm and outlet orifices 210and 212 had diameters of 0.15 mm.

The two solutions were fed to the nozzle at constant rates such thatthey both finished being fed to the nozzle at the same time.

Table 1 and Table 2 show the spray dryer atomization air pressure andoutlet air temperature, the quantitative composition of exampleformulations, a description of the particle morphology, the moisturecontent, particle size, and delivered dose efficiency or MMAD of theresultant powders. Table 1 examples were spray dried using the nozzleillustrated in FIG. 2, whereas Table 2 examples were spray dried usingthe nozzle illustrated in FIG. 3.

                                      TABLE 1                                     __________________________________________________________________________    Batch No., Formula No.                 Particle                               (Spray Dryer Atomization Air                                                                              Particle                                                                            Moisture                                                                           Size                                   Pressure/Outlet Air Temperature)                                                             Quantitative Composition                                                                   Morphology                                                                          Content                                                                            (μm)                                                                           Delivered Dose                     __________________________________________________________________________                                               Efficiency                         329-44         Budesonide                                                                            75 mg                                                                              Slightly                                                                            0.76%                                                                              2.11                                                                              42.0% (RSD = 25)                   B-13           Ethanol 25 ml                                                                              wrinkled                                          (20PSI/76° C.)                                                                        Lactose 1425                                                                             mg                                                                              spheres                                                          DI water                                                                              25 ml                                                  329-47         Budesonide                                                                            50 mg      1.09%                                                                              1.99                                                                              49.5% (RSD = 16)                   B-14           9:1 Acetone:water                                                                     1.25                                                                             ml                                                  (40PSI/77° C.)                                                                        Lactose 950                                                                              mg                                                                 DI water                                                                              98.75                                                                            ml                                                  __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Batch No., Formula No.,               Particle                                                                          Powder                              (Spray Drier Atomization Air                                                                             Particle                                                                            Moisture                                                                           Size                                                                              MMAD                                Pressure/Outlet Air Temperature)                                                             Quantitative Composition                                                                  morphology                                                                          Content                                                                            (μm)                                                                           (μm)                             __________________________________________________________________________    446-63E-S      Budesonide                                                                          187.5                                                                             mg                                                                              Smooth                                                                              0.81%                                                                              1.34 μm                                                                        2.41                                B-38           Ethanol                                                                             62.5                                                                              ml                                                                              irregular                                          (40PSI/77° C.)                                                                        Lactose                                                                             656.25                                                                            mg                                                                              spheres                                                           NaCl  656.25                                                                            mg                                                                  DI Water                                                                            12.5                                                                              ml                                                   529-44B-S      Budesonide                                                                          165 mg      1.16%                                                                              1.33 μm                                                                        2.68                                B-48           Acetone                                                                             55  ml                                                   (30PSI/77° C.)                                                                        Lactose                                                                             577.5                                                                             mg                                                                  NaCl  577.5                                                                             mg                                                                  DI Water                                                                            11  ml                                                   __________________________________________________________________________

Although the foregoing invention has been described in some detail byway of illustration and example, for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

What is claimed is:
 1. A method for preparing a dry powder composition,said method comprising:preparing an aqueous solution of a hydrophiliccomponent; preparing an organic solution of a hydrophobic component inan organic solvent; and delivering the aqueous solution containing thehydrophilic component to an atomizer; delivering the organic solutioncontaining the hydrophobic solution to the atomizer separately from theaqueous solution containing the hydrophilic solution; atomizing the twosolutions together in the atomizer to produce droplets containing bothsolutions; spray drying the droplets of the aqueous solution and theorganic solution to form dry particles comprising a mixture of thehydrophilic and hydrophobic component.
 2. A method as in claim 1,wherein the hydrophilic component has a concentration in the aqueoussolution from 1 mg/ml to 100 mg/ml.
 3. A method as in claim 2, whereinthe hydrophobic component has a solubility of at least 0.01 mg/ml in theorganic solvent.
 4. A method as in claim 3, wherein the hydrophobiccomponent has a concentration in the range from 0.01 mg/ml to 10 mg/mlin the organic solvent.
 5. A method as in claim 1, wherein the organicsolvent is selected from the group consisting of alcohols, ketones,ethers, aldehydes, hydrocarbons, and polar aprotic solvents and mixturesthereof.
 6. A method as in claim 1, wherein the aqueous solution and theorganic solution are atomized using a common nozzle.
 7. A method as inclaim 6, wherein the nozzle is a coaxial spray nozzle.
 8. A method as inclaim 1, wherein the hydrophobic component comprises a hydrophobic drug.9. A method as in claim 8, wherein the hydrophobic drug is a steroidselected from the group consisting of budesonide, testosterone,progesterone, estrogen, flunisolide, triamcinolone, beclomethasone,betamethasone, dexamethasone, fluticasone, methylprednisolone,prednisone, hydrocortisone.
 10. A method as in claim 8, wherein thehydrophobic drug comprises a peptide, a retinoid, vitamin D, vitamin E,vitamin K, precursors and derivatives of these vitamins, aprostaglandin, a leukotriene, tetrahydrocannabinol, lung surfactantlipid, an antioxidant, a hydrophobic antibiotic, and a chemotherapeuticdrug.
 11. A method as in claim 1, wherein the hydrophilic componentcomprises an excipient for the hydrophobic drug.
 12. A method as inclaim 11, wherein the hydrophilic excipient comprises a materialselected from the group consisting of lactose, sodium citrate, mannitol,povidone, pectin, citric acid, sodium chloride, and mixtures thereof.13. A method as in claim 1, further comprising screening the spray driedparticles to disrupt agglomerates.
 14. A method as in claim 1, furthercomprising:measuring a single dosage of the dry powder; and sealing thesingle dosage in a package.
 15. A dry powder composition preparedaccording to claim
 1. 16. A unit dose of a dry powder compositioncomprising a unit dose receptacle having a therapeutically effectiveamount of a dry powder composition prepared according to claim
 1. 17. Amethod for aerosolizing a dry powder composition said methodcomprising:providing an amount of a dry powder composition preparedaccording to claim 1; and dispersing the dry powder composition into aflowing gas stream.